BACKGROUND AND PURPOSE: In relapsing-remitting MS
patients, lower serum vitamin D concentrations are associated with
higher relapse risk. In a number of conditions, low vitamin D has been
associated with fatigue. Pregnant women are at particular risk for
vitamin D insufficiency. Our objective was to investigate whether
vitamin D status is associated with postpartum relapse and quality of
life during pregnancy.METHODS:Forty-three pregnant
relapsing-remitting MS patients and 21 pregnant controls were seen at
regular times before, during and after pregnancy. At every clinical
assessment visit, samples for 25-hydroxyvitamin D (25(OH)D) measurements
and quality of life questionnaires were taken.RESULTS:Lower 25(OH)D
concentrations were not associated with postpartum relapse risk.
Pregnancy 25(OH)D levels of patients and controls were not significantly
different. In controls, but not patients, higher 25(OH)D concentrations
were correlated with better general health, social functioning and
mental health, but not with vitality.CONCLUSION:Low vitamin D levels
are not associated with postpartum relapse. In pregnant MS patients,
vitamin D levels are similar to levels in healthy women and are not
associated with quality of life. Therefore, with regard to quality of
life and postpartum relapse, no arguments were found for advising
pregnant MS patients to take more vitamin D supplements than healthy
women.

This study looks at pregnant women and finds that potential for developing a relapse is unrelated to their vitamin D level. Is this surprising?.

Maybe
not when other sudies look in to the ability of vitamin D we find a
neutriceutical.

However the major
question is: What does vitamin D do to the unborn in pregnant women?
Does this limit MS suceptibility.

Cerebellar abnormalities in early MS: the shredder may be quietly destroying your connections. #ClinicSpeak #MSResearch #MSBlog

"The study below is very interesting in that it is applying new imaging technology to MS. It is using techniques to assess the connections of the so called cerebellar pathways in early MS. The cerebellum is the pathway that is mainly responsible for balance and coordination. The cerebellum is essential for the timing of movements. When I was at medical school I learnt a mnemonic for the symptoms and signs associated with cerebellar malfunction: VANISHDDD."

V = vertigo; dizziness with a feeling of rotation.

A = ataxia; unsteadiness of gait. We test for this by asking you to heel-toe walk on a straight line with your eyes open and the with your eyes closed.

N = nystagmus; jerking movements of the eyes, particularly when looking either left or right. Often the eyes jerk from when looking straight ahead; if you look closely there is a slow drift and a rapid correction. Neurologists call these movements square-wave jerks.

I = intention tremor; tremor of the fingers or hands when doing some; the tremor gets worse as you approach the target.

S = slurred speech; the speech sounds as if you have too much to drink. In fact alcohol is cerebellar toxin and a large number of the symptoms and signs of alcohol intoxication are due to cerebellar dysfunction.

H = hypotonia; this is when passive movements of the legs and arms suggest they are floppy.

D = dysmetria; difficulty judging distances. For example when you try and touch something you stop too early or you move beyond the object. If you have ever been asked to do the finger-nose test you point past the finger (past-pointing) or you miss your nose.

D = dysdiadochokinesia; this is a big word for clumsy movements. You may have been asked to do rapid alternating movements of the hands. If you can't do these and/or they are slow and clumsy we call this dysdiadochokinesia.

D = dysarthria; this is medical term for slurred speech.

Another sign should be cognitive impairment. Cognitive impairment is very common in MSers with severe cerebellar signs. In my experience it manifests as difficulty sequencing memories; cerebellar patients are very vague about when things happened and how they happened in relation to each other. Some of you may recognise these symptoms."

Cerebellum

"What this study shows that in early MS, compared to controls, there are abnormalities in relation to the cerebellar connections. These abnormalities are found in early MS when there are no, or very few subtle signs of cerebellar dysfunction. What it is showing that MSers are able to compensate for the damage in their cerebellar pathways by using their reserve capacity or adaptations in other neuronal systems. These processes are called plasticity in neurospeak. Plasticity or the ability of the nervous system to cope with damage and is what keeps progressive MS at bay. Once the reserve capacity becomes exhausted then you manifest fixed neurological deficits that tend to get worse with time. This is another indication that we simply can't rely on the clinical examination to tell us that the brain and spinal cord are normal. What we need to use are methods, such as the MRI study below, to interrogate the functional reserve of the neuronal systems. It should be our therapeutic aim to protect and enhance this reserve to keep progressive disease at bay for as long as possible. The latter is a central theme of my asynchronous progressive MS hypothesis, i.e. there are multiple therapeutic windows to target even if once system has already exhausted its reserve capacity. For example, someone may have entered clinically apparent secondary progressive MS phase with weakness and difficulty walking in their legs, but still have very good upper limb and cognitive function. Should we simply write-off their upper limb function and cognition because their lower limb reserve capacity is exhausted? Of course not; this is why we have to design new trials for progressive MS that use outcome measures that focus on neuronal systems with reserve capacity."

"This post reminds me that we should be hearing about the headline results from the fingolimod PPMS trial very soon; I was told there would be a press release either in the last week of November or the first week of December. I wonder if my prediction of the results will be correct; this prediction is based on the asynchronous progressive MS and therapeutic lag hypotheses."

Background: Cerebellar pathology occurs in late multiple sclerosis (MS) but little is known about cerebellar changes during early disease stages. In this study, we propose a new multicontrast “connectometry” approach to assess the structural and functional integrity of cerebellar networks and connectivity in early MS.

Methods: We used diffusion spectrum and resting-state functional MRI (rs-fMRI) to establish the structural and functional cerebellar connectomes in 28 early relapsing-remitting MS patients and 16 healthy controls (HC). We performed multicontrast “connectometry” by quantifying multiple MRI parameters along the structural tracts (generalized fractional anisotropy-GFA, T1/T2 relaxation times and magnetization transfer ratio) and functional connectivity measures. Subsequently, we assessed multivariate differences in local connections and network properties between MS and HC subjects; finally, we correlated detected alterations with lesion load, disease duration, and clinical scores.

Saturday, 29 November 2014

Background: MS is a complex disease of neurological disability, affecting more than 300 out of every one million people in the world.

Aim: The purpose of the study was to evaluate the therapeutic effects of human umbilical cord-derived mesenchymal stem cell (hUC-MSC) transplantation in MSers.

Methods: 23 MSers were enrolled in this study and 13 of them were given hUC-MSC therapy at the same time as anti-inflammatory treatment, whereas the control patients received the anti-inflammatory treatment only. Treatment schedule included 1,000 mg/kg of methylprednisolone i.v. daily for 3 days and then 500 mg/kg for 2 days, followed by oral prednisone 1mg/kg/day for 10 days. The dosage of prednisone was then reduced by 5mg every two weeks until reaching a 5mg/day maintenance dosage. Intravenous infusion of hUC-MSCs was applied three times in a 6 week period for each patient. The overall symptoms of the hUC-MSC treated patients improved compared to patients in the control group. Both the EDSS scores and relapse occurrence were significantly lower than those of the control patients. Inflammatory cytokines were assessed, and the data demonstrated a shift from Th1 to Th2 immunity in hUC-MSC treated patients. Our data demonstrated a high potential for hUC-MSC treatment of MS

There you have it. Stem cells seem to have benefit but based on most data I have seen they do not really turn into anything and dies within a few days but that may make enough growth factors to promote repair

Questions to ask yourself when interpreting the alemtuzumab phase 3 trial data. #LACTRIMS #MSBlog #MSResearch"As promised are the slides from the Genzyme symposium presented yesterday at LACTRIMS. The presentations were very data heavy and to help the attendees digest the data in their own time my co-presenter Professor Flavia Nelson has agreed for her slides to be uploaded with mine; thank you."

"To make a data heavy alemtuzumab presentation clinically relevant I tried to present the data in the context of the following questions:

How early is early?

What about the patient wanting to have children?

Is it realistic to expect improvement in disability?

How durable is the treatment response to alemtuzumab?

Do you tell your patients about brain atrophy (end-organ damage)?

Can you de-risk alemtuzumab treatment; how to deal with infusion reactions, infections and secondary autoimmunity?

It is reassuring to note that most LATAM neurologists have, or soon will have, access to alemtuzumab to treat their patients."

"I would like to thank my Peruvian hosts; such hospitable people with a truly amazing history and culture."

Friday, 28 November 2014

More data showing early access to DMTs is better than delayed access. #ClinicSpeak #MSBlog #MSResearch"The Scandinavian countries are blessed with data and the ability to collect it. Why? I suspect because it is cultural and happens at a national level. In Sweden virtually every MSer belongs to the national register and data is collected and added to this register annually. This substudy of the largest treating MS centre in Sweden demonstrates that early access to DMTs reduces your chances of a poor outcome; i.e. of reaching EDSS 4 or beyond. An EDSS of 4 or higher indicates walking difficulties and most in the field (but not me) think this is a good proxy for the onset of SPMS. This is just another data set confirming that early access to DMTs changes the long-term natural history of MS and delays you reaching certain disability milestones. As most of this data was from the injectable DMT era (interferon-beta and glatiramer acetate) it is likely to get better with time with the emergence of more effective treatments."

"Why don't I think an EDSS 4 is a proxy for SPMS? This is because of therapeutic lag and the asynchronous progressive MS hypotheses that I have discussed many time before on this blog. I think the concept of SPMS is an academic construct to explain a clinical phenotype and is not backed by biology. Most of us accept that the pathological substrates that underpin progressive MS are demyelination, neuroaxonal loss and gliosis, which when combined with a failure of neuronal reserve manifests as progressive MS clinically. If we accept a biological definition of progression then progressive MS is present from the start of the disease, in fact it probably starts before you present with your first clinical attack or symptoms. New data shows that RISers (people with radiologically-isolated or asymptomatic MS) already have brain atrophy. In my opinion, any treatment that reduces or prevents these pathological mechanisms that drive progression will delay the onset of clinically-defined SPMS."

"The problem with our clinical definitions is that they are so unreliable and are a moving target. In the pre-DMT era SPMS used to be diagnosed when MSers had EDSS scores of 2.0-2.5. Now that we have DMTs most people will only diagnose SPMS when MSers are more disabled with EDSS scores above 4.0. Why? Simply because funders will only pay for DMTs in MSers who have relapsing disease. As soon you label someone with SPMS it makes it difficult to prescribe DMTs. How can we rely on a clinical definition of SPMS, when we are continuously changing the definition?"
"I have sat on countless steering committees that have tried to operationalise time to onset of SPMS as a clinical outcome. It has not been possible to reach any consensus. The proposal to use an EDSS milestone instead, for example time to confirmed disability progression to EDSS 4.0, also has problems. Why 4.0? I agree that most natural history studies suggest that once MSers hit 4.0 the disease progresses relentlessly regardless of whether or not they have superimposed relapses, or not. I am not sure if this is correct when you are on a DMT. A lot of emerging data suggests that things are very different in the DMT era; we cannot rely on the natural history data to make decisions about the onset of SPMS. For one we need to consider the concept of the therapeutic lag; this based on the hypothesis that in MSers with reduced reserve capacity, disease progression occurring now has been primed by inflammation from one to two years ago. If you switch off inflammation now you need to wait three to five years to see an impact."

"The other problem I have is that our definition of SPMS tends to be defined by lower limb motor activity. What about the other neurological systems? This is why I think we need to seriously rethink our definition of what is progressive MS."

"There is little doubt in my mind that if DMTs reduce end-organ damage they will delay disability progression and delay the clinical onset of SPMS, however, you want to define it. Apart from the British Columbia register all the other data sets showed that DMTs delayed the onset of clinically-defined SPMS. The issue for purists is that this data is not collected in randomised trials and is therefore unacceptable. What do they want?"

"When I did my PhD I worked in Marc Feldmann's and Tini Maini's laboratory; this duo pioneered the clincal development of anti-TNF (tumour necrosis factor alpha) therapy in rheumatoid arthritis. Anti-TNF therapy switched off the inflammation and made RAers feel well. This triggered a debate whether or not this would prevent end-organ joint damage and the need for joint replacement therapy in the future. Marc Feldmann had no doubt about the longterm impact of these therapies. Why? He understood the biology of RA and knew that inflammation was the driver of end-organ damage; switch it off and you protect joints. Marc has now been proved correct; it is clear that the number of joint replacements required in RAers has plummeted. Maybe we should start counting walking sticks and wheelchair numbers? We already do; EDSS 6.0 and 7.0 are measured surrogates for sticks and chairs. If DMTs are reducing time to EDSS 6.0 and 7.0 they are reducing the needs for sticks and chairs. If the clinical onset of SPMS is linked to EDSS progression then DMTs are delaying the onset of SPMS."

"Unfortunately, unlike joint replacement therapies in RA, or renal dialysis, or transplantation in other end-stage organ failures, we can't replace the brain and spinal cord, nor can we restore their function when they fail. It is time to think of DMTs as preventive therapies; they are preventing the rate MSers acquire disability. We shouldn't get too bogged down in how we define this; particularly clinically. We need to remember the iceberg analogy."

Background: Multiple sclerosis (MS) is a chronic disease of the central nervous system. One of the major questions concerning the clinical progression of MS, still insufficiently elaborated or confirmed, is if it can be slowed down or augmented by external factors. Immunomodulatory treatment is a disease modifiable factor shown to influence disease progression of various medical conditions.Objective: To investigate if treatment affects the long-term clinical progression of MS, measured as time from diagnosis to score of 4 or higher of Expanded Disability Status Scale (EDSS).Methods: Longitudinal, prospective data concerning treatment status and EDSS were collected by health professionals in the Swedish MS Registry. Study cohort comprised new diagnosed MS patients at Karolinska Hospital between 2001 and 2005. Survival analysis adjusted for suspected confounders was used with the outcome variable time from diagnosis to EDSS ≥4.Results: Early treatment was correlated with longer time from diagnosis to EDSS ≥4 (HR: 1.77; 95 % CI: 1.15–2.73; p = 0.01). Additionally, the influence of the covariates—age at onset and the baseline EDSS, which were statistically significant with hazard ratios of 1.03 and 2.1, respectively, was found.Conclusion: Early treatment was associated with a better clinical outcome.CoI: multiple

The aetiology of multiple sclerosis (MS) is currently unknown. However, one potential mechanism involved in the disease may be excitotoxicity. The elevation of glutamate in cerebrospinal fluid, as well as changes in the expression of glutamate receptors (iGluRs and mGluRs) and excitatory amino acid transporters (EAATs), have been observed in the brains of MS patients and animals subjected to experimental autoimmune encephalomyelitis (EAE), which is the predominant animal model used to investigate the pathophysiology of MS. In the present paper, the effects of glutamatergic receptor antagonists, including amantadine, memantine, LY 367583, and MPEP, on glutamate transport, the expression of mRNA of glutamate transporters (EAATs), the kinetic parameters of ligand binding to N-methyl-D-aspartate (NMDA) receptors, and the morphology of nerve endings in EAE rat brains were investigated. The extracellular level of glutamate in the brain is primarily regulated by astrocytic glutamate transporter 1 (GLT-1) and glutamate-aspartate transporter (GLAST). Excess glutamate is taken up from the synaptic space and metabolized by astrocytes. Thus, the extracellular level of glutamate decreases, which protects neurons from excitotoxicity. Our investigations showed changes in the expression of EAAT mRNA, glutamate transport (uptake and release) by synaptosomal and glial plasmalemmal vesicle fractions, and ligand binding to NMDA receptors; these effects were partially reversed after the treatment of EAE rats with the NMDA antagonists amantadine and memantine. These results suggest that disturbances in these mechanisms may play a role in the processes associated with glutamate excitotoxicity and the progressive brain damage in EAE.

Excitotoxicity is a concept that developed from the stroke field. There you have a blood clot that blocks the blood vessel and causes the nerves to die because of lack of oxygen (ischaemia). The penumbra is the area surrounding an ischaemic event, Immediately following the event, blood flow and therefore oxygen transport is reduced locally, leading to hypoxia of the cells near the location of the original insult. This can lead to hypoxic cell death (infarction) and amplify the original damage from the ischemia; however, the penumbra area may remain viable for several hours after an ischemic event due to the collateral arteries that supply the penumbral zone. However within the ischemic penumbra nerves start to fire due to glutamate release and cause excitotoxity.Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate. This occurs when receptors for the excitatory neurotransmitter glutamate (glutamate receptors) such as the NMDA receptor and AMPA receptor are overactivated by glutamatergic storm. Excitotoxins like NMDA and kainic acid which bind to these receptors, as well as pathologically high levels of glutamate, can cause excitotoxicity by allowing high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes that trigger cell suicide.

Low Ca2+ buffering and excitotoxicity under physiological stress and pathophysiological conditions in motor neuron (MNs). Low Ca2+ buffering in S vulnerable nerves are exposes mitochondria to higher Ca2+ loads compared to highly buffered cells. Under normal physiological conditions, the neurotransmitter opens glutamate, NMDA and AMPA receptor channels, and voltage dependent Ca2+ channels (VDCC) with high glutamate release, which is taken up again by EAAT1 and EAAT2. This results in a small rise in intracellular calcium that can be buffered in the cell. In MS high Ca2+ loads and increased risk for mitochondrial damage. This triggers the mitochondrial production of reactive oxygen species (ROS), which then inhibit glial EAAT2 function. This leads to further increases in the glutamate concentration at the synapse and further rises in postsynaptic calcium levels, contributing to the selective vulnerability of nerves

The Excitatory amino-acid transporters (EAATs), also known as glutamate transporters, EAATs serve to terminate the excitatory signal by removal (uptake) of glutamate from the neuronal synaptic cleft into neuroglia and neurons. These transporters play the important role of regulating concentrations of glutamate in the extracellular space by transporting it along with other ions across cellular membranes.After glutamate is released as the result of an action potential, glutamate transporters quickly remove it from the extracellular space to keep its levels low, thereby terminating the synaptic transmission. Without the activity of glutamate transporters, glutamate would build up and kill cells by excitotoxicity. In Stroke these transporters may go into reverse mode and add to the problem. It has been known for quite some time that there are alterations with the transporters in MS

This study shows that there are problems in the EAAT that may be rectified by blockade of NMDA glutamate receptors. Doing this in EAE can save nerves and it may also occur in MS but the results of treating with NMDA antagonists have been equivocal. Also other studies have suggested blockade of AMPA the other form of glutamate receptor could be neuroprotective however studies in MS have not been reported.....I suspect because blockade of AMPA is toxic...strong blockers are the wrong way to go they easily kills rodents and has sedating side effects and also surprisingly for an antagonist it causes "tolerance" so it stops working and this may contribute to NMDA not being as effective as one may think. It is a weak blocker at least.

ProfG came up with the concept of the "Inflammatory Penumbra" for problems of damage in MS

Here we have damage around the vessel that occurs due to inflammation and part of this problem will be excitotoxicity.

However there are other ways to get at the problem of the penumbra and also the problems of progression. We have invented some new drugs that may do just that. However as you know these

will be years for reaching MS. So in the shorter term we have to use what is available.

In active inflammation, we have shown experimentally that there is a window of opportunity to make an impact in this penumbra and have used this knowledge to test the idea.

Thursday, 27 November 2014

The problem of chickenpox and shingles on fingolimod and other DMTs. #ClinicSpeak #MSBlog #MSResearch

"The article below on Varicella-zoster virus (VZV) infection in MSers on fingolimod is timely and very relevant to field. VZV is a herpes virus that causes chicken pox and once infected is responsible for recurrent localised infections called shingles. This study is important as there have been two deaths on fingolimod due disseminated chicken pox infection. One MSer had not had chicken pox as a child and the other had very low level of antibodies. This is why we pre-screen all our patients prior to starting fingolimod to make sure they have got antibodies against the virus; if they don't we vaccinate them and delay starting fingolimod for 4-6 weeks. However, even if you have previously had chicken pox, and have antibodies, you are at risk of getting shingles on fingolimod. So you need to be vigilant of symptoms that might suggest reactivation of the virus."

"Early symptoms of shingles may include headache, photophobia (sensitivity to light) and non-specific flu-like symptoms. You may feel itching, tingling, or pain in a band, strip, or small area of skin, where the shingles rash will appear several days or weeks later. The rash quickly turns into small blisters, that burst and then scab over, and finally clear up over a few weeks. The rash is often very painful and may be itchy. The rash occurs in a typical dermatomal distribution; a big word to describe the area of skin supplied by a single nerve root from the brain or spinal cord. This occurs because the virus lives inside the neurons and when it reactivates it travels down the nerve to the area of skin supplied by those specific nerve. This is why the rash wrap around either the left or right side of your body or appear on your face around one eye. It is possible to have more than one area of rash on your body, but this is quite rare."

"Shingles develops in stages: the prodromal stage (before the rash appears) is characterised by pain, burning, tickling, tingling, and/or numbness in the area supplied by the affected nerve. This phase typically last several days before the rash appears. Flu-like symptoms usually develop just before the rash appears. Depending where the shingles is located you may experience swelling and tenderness of the local lymph nodes draining that area. The active stage is when the rash and blisters appear on teh skin; typically in a band, strip, or small area. The rash can appear anywhere on the body; it is usually located to only one side of the body. Soon after the rash appears small blisters will form with clear fluid inside them. The fluid may become cloudy after a few days; the cloudiness is due to white blood cells attacking the virus. Rarely, some people won't get a rash, or the rash will be very small or mild and missed. It is often missed when it occurs in the hair, ear or between the cheeks of you buttocks. When the rash occur on the forehead, cheek, nose, and around one eye (so called herpes zoster ophthalmicus), it may spread to infect the cornea of the eye and threaten your sight. This is really a medical emergency and need urgent treatment. The pain of shingles can be excruciating and is often described as if someone is piercing your skin with needles. Once the blisters break open, they tend to ooze, and crust over in about 5 days. The rash heals in about 2 to 4 weeks and often leaves some scaring or loss of pigment. The area of the scarring is typically anaesthetic; i.e. when you prick it with a needle you can't feel pain. The latter is clinical sign we use to diagnose post-herpetic scarring. In a significant number of affected people they are left with post-herpetic neuralgia; chronic pain in the distribution of the nerve affected by the shingles. Post-herpetic neuralgia is the most common complication and typically last months or years. Symptoms of post-herpetic neuralgia are aching, burning and stabbing pain in the area of the earlier shingles rash. Persistent neuralgia may last years and the affected area could be sensitive to touch. In some cases post-herpetic neuralgia can be so severe that affects activities of daily living such as eating, sleep and physical functioning; when it is this bad it is usually associated with depression."

"If you are on fingolimod, or any othe DMT, and develop shingles you need to contact you doctor so that you can be started on anti-viral drugs. We use acyclovir/aciclovir, valacyclovir/valaciclovir or famcyclovir/famciclovir to treat shingles; Professor Julian Gold who works with us and has extensive eperience with shingles as an HIV infectious disease expert favours famcyclovir due it long half-life inside cells. All these drugs are now off patent so are relatively cheap."

IMPORTANCE: Varicella-zoster virus (VZV) infections increasingly are reported in MSers and constitute an area of significant concern, especially with the advent of more disease-modifying treatments in MS that affect T-cell-mediated immunity.

OBJECTIVE: To assess the incidence, risk factors, and clinical characteristics of VZV infections in fingolimod-treated MSers and provide recommendations for prevention and management.

DESIGN, SETTING, AND PARTICIPANTS: Rates of VZV infections in fingolimod clinical trials are based on pooled data from the completed controlled phases 2 and 3 studies (3916 participants) and ongoing uncontrolled extension phases (3553 participants). Male and female MSers aged 18 through 55 years (18-60 years for the phase 2 studies) and diagnosed as having relapsing-remitting MS were eligible to participate in these studies. In the postmarketing setting, reporting rates since 2010 were evaluated.

INTERVENTIONS: In clinical trials, MSers received fingolimod at a dosage of 0.5 or 1.25 mg/d, interferon beta-1a, or placebo. In the postmarketing setting, all MSers received fingolimod, 0.5 mg/d (total exposure of 54 000 patient-years at the time of analysis).

RESULTS: Overall, in clinical trials, VZV rates of infection were low but higher with fingolimod compared with placebo (11 vs 6 per 1000 MSer-years). A similar rate was confirmed in the ongoing extension studies. Rates reported in the postmarketing settings were comparable (7 per 1000 MSer-years) and remained stable over time. Disproportionality in reporting herpes zoster infection was higher for MSers receiving fingolimod compared with those receiving other disease-modifying treatments (empirical Bayes geometric mean, 2.57 [90% CI, 2.26-2.91]); the proportion of serious herpes zoster infections was not higher than the proportion for other treatments (empirical Bayes geometric mean, 1.88 [90% CI, 0.87-3.70]). Corticosteroid treatment for relapses might be a risk factor for VZV reactivation.

CONCLUSIONS AND RELEVANCE: Rates of VZV infections in clinical trials were low with fingolimod, 0.5 mg/d, but higher than in placebo recipients. Rates reported in the postmarketing setting are comparable. We found no sign of risk accumulation with longer exposure. Serious or complicated cases of herpes zoster were uncommon. We recommend establishing the MSer's VZV immune status before initiating fingolimod therapy and immunization for MSers susceptible to primary VZV infection. Routine antiviral prophylaxis is not needed, but using concomitant pulsed corticosteroid therapy beyond 3 to 5 days requires an individual risk-benefit assessment. Vigilance to identify early VZV symptoms is important to allow timely antiviral treatment.

The most accurate predictor of the subsequent development of multiple sclerosis in clinically isolated syndrome is the presence of lesions at magnetic resonance imaging. We used in vivo positron emission tomography with 11C-(R)-PK11195, a biomarker of activated microglia, to investigate the normal-appearing white matter and grey matter of subjects with clinically isolated syndrome to explore its role in the development of multiple sclerosis. Eighteen clinically isolated syndrome and eight healthy control subjects were recruited. Baseline assessment included: history, neurological examination, expanded disability status scale, magnetic resonance imaging and PK11195-positron emission tomography scans. All assessments except the PK11195-positron emission tomography scan were repeated over 2 years.

We show a global increase of normal-appearing white matter PK11195 binding in clinically isolated syndrome subjects compared with healthy controls (P = 0.014). Clinically isolated syndrome subjects with T2 magnetic resonance imaging lesions (as a indicator of MS diagnosis) had higher PK11195 binding in normal-appearing white matter (P = 0.009) and their normal-appearing white matter PK11195 binding levels correlated with the Expanded Disability Status Scale (P = 0.007; r = 0.672). At 2 years those who developed dissemination in space or multiple sclerosis, had higher PK11195 binding in normal-appearing white matter at baseline (P = 0.007 and P = 0.048, respectively). Central grey matter PK11195 binding was increased in subjects with clinically isolated syndrome compared to healthy controls but no difference was found in cortical grey matter PK11195 binding. Microglial activation in clinically isolated syndrome normal-appearing white matter is diffusely increased compared with healthy control subjects and is further increased in those who have magnetic resonance imaging lesions. Furthermore microglial activation in clinically isolated syndrome normal-appearing white matter is also higher in those subjects who developed multiple sclerosis at 2 years. Our finding, if replicated in a larger study, could be of prognostic value and aid early treatment decisions in clinically isolated syndrome.

This is further evidence that on balance "hot" microglia detected by positron emission tomography using a radioactive (radioactive carbon) probe (PK11195) that binding microglia. There was evidence of microglial activation around the myelin and this was more noticeable at the first major symptom in people whoconvert to MS.

Wednesday, 26 November 2014

How to measure scientific impact in the era of pop science? Will altmetric turn out to be a curse? #MSPolitics #MSResearch #MSBlog

"Research impact; what does it mean? We as researchers are increasingly getting judged, and then hired and fired, based on our research performance. The 2014 UK research excellence framework (REF) include a metric on impact. We are told that going forward research impact is going to be increasingly important. It is a great pity we can't rely in the tried and tested way of assessing research impact based on citations and longevity of research over time. Short-term impact may turn out to be a fad; i.e. pop science, and disappear with time. In comparison transformational discoveries stand the the test of time; they are adopted and become entrenched in our culture."

"If you ask me this paper will only have real impact if what we have described is real, i.e. confirmed, and it leads to new insights and treatments for multiple sclerosis. What is needed and is currently lacking is the time vector? As I sit on my sabbatical in Lima, Peru, at the LACTRIMS meeting contemplating life, the universe and everything, it is essential for us to take the HIV-MS association as a starting point to look at MS in a different way. Could this observation that started off with an anecdotal observation that someone's MS went into long-term remission after he went onto antiretroviral therapy having become HIV-positive. Could the association between MS and HIV be the clue to the cause of MS and autoimmunity in general? What we really need is; (1) for a register of people who have MS and HIV who are on anti-retrovirals to see what happens to their MS; (2) the results of the INSPIRE trial; (3) and a full-blown well-powered phase 2 trial of HAART (highly-active antiretroviral therapy) in MS."

More evidence of the meaning and validity of ALMs and altmetrics, coupled with greater consistency and transparency in their presentation, would enable research funders to explore their potential value and identify appropriate use cases.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease triggered by infection with the human gliotropic JC virus (JCV). Due to the human-selective nature of the virus, there are no animal models available to investigate JCV pathogenesis. To address this issue, we developed mice with humanized white matter by engrafting human glial progenitor cells (GPCs) into neonatal (post-birth) immunodeficient (no effective immune system so it will not reject human cells) and myelin-deficient mice. The human cells then produce the myelin in the mice. Intracerebral delivery (brain injection) of JCV resulted in infection and subsequent demyelination of these mice. Human GPCs and astrocytes were infected more readily than oligodendrocytes, and viral replication was noted primarily in human astrocytes and GPCs rather than oligodendrocytes, which instead expressed early viral antigens and exhibited death. Engraftment of human GPCs in normally myelinated and immunodeficient mice resulted in humanized white matter that had human astrocytes and GPCs. JCV effectively propagated in these mice, which indicates that astroglial infection is sufficient for JCV spread. Sequencing revealed progressive mutation of the JCV capsid protein VP1 after infection, suggesting that PML may evolve with active infection. These results indicate that the principal CNS targets for JCV infection are astrocytes and GPCs and that infection is associated with progressive mutation, while demyelination is a secondary occurrence, following oligodendroglial apoptosis. More broadly, this study provides a model by which to further assess the biology and treatment of human-specific gliotropic viruses.

Demyelination after JC virus has been mooted as a main problem in PML, however in this study they got a mouse and made it contain human glial cells and mylein and it suggests that infection of astrocytes is the main problem and that oligodendrocyte is a later casualty. This now gives a tool to hunt for treatments to JCV infection

Methods.We performed qualitative interviews (n = 5) and a survey (n = 104) with MS patients regarding MRI patient information, and basic MRI knowledge. Based on these findings an interactive training program of 2 hours was developed and piloted in n = 26 patients.

Results Interview analyses showed that patients often feel lost in the MRI scanner and left alone with MRI results and images while 90% of patients in the survey expressed a high interest in MRI education. Knowledge on MRI issues was fair with some important knowledge gaps. Major information interests were relevance of lesions as well as the prognostic and diagnostic value of MRI results. The education program was highly appreciated and resulted in a substantial knowledge increase. Patients reported that, based on the program, they felt more competent to engage in encounters with their physicians.

Conclusion. This work strongly supports the further development of an evidence-based MRI education program for MS patients to enhance participation in health-care.

I have never had an MRI, so I can't speak from any position of knowledge, but it appears that MRI baffles you just like it baffles me. But education can help you understand these images.

Ask an MRIer to explain what MRI really is and what each of the imaging modalities actually shows, eg. T1, T2, gadolinium, MTR, FLAIR, DTI, etc, etc and half an hour later you are often still no wiser. You get the gist by little appears to be concrete fact.

One MRI physicist once said of the scientist that "you lot will never understand this" cos the mathematics was too complex. MRI has revolutionised the diagnosis and monitoring of MS, but many of the outcomes, still have no definitive pathological outcomes so we hear associating this and prediction that.

Maybe some MRIers would like to do some guest posts to explain....Doctor Klaus? or are there some websites that you find particularly useful.

BACKGROUND:Fingolimod inhibits lymphocyte egress from lymphoid tissues, thus altering the composition of the peripheral lymphocyte pool ofmultiple sclerosis patients.OBJECTIVE:The objective of this paper is to evaluate whether fingolimod determines a decrease of newly produced T- and B-lymphocytes in the blood and a reduction in the T-cell receptor repertoire diversity that may affect immune surveillance.METHODS:Blood samples were obtained from multiple sclerosis patients before fingolimod therapy initiation and then after six and 12 months. Newly produced T and B lymphocytes were measured by quantifying T-cell receptor excision circles and K-deleting recombination excision circles by real-time PCR, while recent thymic emigrants, naive CD8+ lymphocytes, immature and naive B cells were determined by immune phenotyping. T-cell receptor repertoire was analyzed by complementarity determining region 3 spectratyping.RESULTS:Newly produced T and B lymphocytes were significantly reduced in peripheral blood of fingolimod-treated patients. The decrease was particularly evident in the T-cell compartment. T-cell repertoire restrictions, already present before therapy, significantly increased after 12 months of treatment.CONCLUSIONS: These results do not have direct clinical implications but they may be useful for further understanding the mode of action of this immunotherapy for multiple sclerosis patients.

T cells recognise their targets using the T cell receptor, This repertoire determines what you can recognise, whether this is a pathogen or a self protein, In this study they assessed receptor diversity before and after fingolimod and it was found to go down following treatment with Gilenya. The alpha and beta chains of the T cell receptor is formed in the thymus buut splicing gene products together and when they do this TRECS are formed. During TCR rearrangement processes, unused excised DNA fragments create byproducts termed TCR excision circles (TRECs). They could detect what the T cell receptors were by typing them (Spectratyping). They also looked a the phenotypes of the cells to workout if they were newly formed and immature.

In this study they report that gilenya reduced the repertoire, this would be expected as it blocks naive cells from leaving lymph glands. With a reduced repertoire available it means less potential to react to new targets maybe in the CNS but also to react to infectious agents.

Can we use modeling to do virtual head-2-head studies; the relative efficacy of the orals. #MSBlog #MSResearch #ClinicSpeak

"It is becoming increasingly important to demonstrate efficacy, or
relative efficacy, of one DMT over another so that the cost-effectiveness of
the agents can be assessed and the correct level of reimbursement set. Some European
countries have made this a priority. One particular country has asked for data
on the relative efficacy of fingolimod against the other oral drugs on the
market. Short of doing head-2-head studies the next best thing is to model the
drugs against each other using published data. How do you do this? The most
common method is simply to compare the phase 3 trial outcome data. This is fraught
with problems because of the different type of MSers recruited into these
studies and the different time epochs these studies were performed in. In
addition, the relapse rates, or events, in the comparator or placebo arms differ,
making comparison between relative efficacy rates difficult. The best way to
tackle this is statistically is using modeling. I was somewhat surprised that
there are well-developed methods in statistics for doing this. Why hadn’t the
field of MS embraced these methods earlier? My interest in all things MS got me
invited onto a panel to try modeling the outcome and made me realise why the
10,000 hour rule is so important. The statisticians who worked on this project are simply
amazing and I want to take this opportunity to thank Niklas Bergvall, Richard Nixon, Nikolaos Sfikas and Gary Cutter for
opening my eyes to a new world of statistics that the non-expert like me can
only dream of being able to do. Statisticians are seriously under-appreciated; not anymore in my books. Although the methods are very complicated and it took me a
long time to grasp, they are a major improvement on the
comparative methods we have been using to date to compare trial outcomes.”

“I have tried to explain the principles of the modeling method using the embedded slideshow. Most of the
problems with across trial comparisons relate to differences in the study
population. What we did is simply take all the fingolimod trial data and extract from
it subpopulations of MSers that match the baseline characteristics of the MSers
studied in the Teriflunomide and DMF studies. When asked how these matched sub-populations
from the fingolimod trials did in achieving NEDA (no evident disease activity) and compared them to the published data from the teriflunomide and DMF trials. To do this analysis you need all the raw trial data from the
fingolimod trials to interrogate and you need the published data from the
teriflunomide and DMF studies. You then define characteristics in the study
population that may affect the outcome; these are referred to in stats speak as
covariates. For the analyses we used 8 covariates:

Age

Gender

Previous DMT use

Duration of MS

Number of relapses in the past year

EDSS score at baseline

Number of Gd-enhancing T1 lesions at baseline

Cube root of the total volume of T2 lesions

The modeling method uses a conservative approach in that it penalises our
assumptions to keep things as simple as possible; it does this by trimming the confidence
intervals of the relative risks attributed to each covariate. By doing this you
limit the models complexity and only keep the covariates that affect outcome. For
the non-statisticians reading this post the so called penalisation factor is
called the Akaike information criterion or AIC. We then assessed the model for
its goodness-of-fit using another set of statistical rules before accepting it.
The message I want to get across is that this assessment is no trivial task and
the results are about as close as you can get to a formal head-2-head study
from the data we had in hand. In other words an in silico head-2-head study."

"Why NEDA? It is becoming increasingly clear that NEDA, or a form of
minimal evidence of disease activity (MEDA), is becoming the treatment target
among the vast majority of MSologists, with some well-publicised exceptions
(e.g. the United Kingdom). Therefore it made sense to us this outcome as the results may help guide clinical practice. Interestingly, I second guessed these
results based on the primary outcome data of the clinical trials, but it is nice to see that the model
predicted my assumptions."

"There are limitations to our modeling approach that are based on our assumptions.
For example, we assumed that the outcomes of the trials were influenced by the set
of 8 covariates above; it is likely, that the results could be affected by additional
variables not included in the models, such as the environment at the time these
studies were conducted and/or the neurological practice in countries participating in the studies.
Unfortunately, we can only adjust for known variables and could not account for
subtle unmeasured selection criteria as sources of influence or bias. The other issue is that the way NEDA is reported in these studies is using the baseline or month zero scan. We now rebaseline MSers on DMTs so this analysis will need to be redone when we can access year 2 data only; i.e. NEDA rates after rebaselining at month 12. The current methods put teriflunomide at a disadvantage as it probably takes the longest to start working and it had the most active study subjects based on the event rate in the placebo group. Interestingly, teriflunomide is the only oral DMT to hit significant disability outcomes in both studies, which is why it is level pegging with DMF in our analysis relative to fingolimod. It would be interesting for Genzyme-Sanofi and Biogen-Idec to repeat the same exercise as us using their own data sets; i.e. to triangulate the results. Wouldn't it be interesting if their results were the same or even differed? I would like to challenge them to do the same."

"Will these results affect clinical practice? They are unlikely to in the
UK or Europe, where fingolimod has a 2nd-line license. In the UK you can only use fingolimod after you have failed a 1st-line injectable therapy. I suspect in countries
where fingolimod has a 1st-line license this may affect MSer and
MSologist choice.""As far as MSer-choice goes efficacy is only one factors in
the decision-making process. I always tell patients that it is ‘horses for
courses’; gone are the days when we simply prescribe a drug and leave you on it
for years. We now actively monitor response, or non-response, and if you have
breakthrough disease we change your therapy. Therefore, I think much bigger
differentiators for individuals amongst the oral therapies will be pregnancy,
tolerability, side-effects, adherence and safety issues. As I say this I am also acutely
aware that fingolimod will be the first small molecule oral medication that
comes off patent, which should pave the way for a cheap generic DMT for MSers.
This in my opinion will be the most disruptive factor to face the MS DMT market. Any
guesses on whether or not the EMA will change fingolimod’s license? Let’s hope
so for the sake of MSers. I predict fingolimod will become a 1st-line treatment in Europe long
before 2019 in anticipation of it coming off patent. As always economics is the
trump card; if it wasn’t we wouldn’t have to resort to complex statistical
modeling and posts of this nature.”

"Another disruptor is cladribine; we didn't include it in this analysis as it does not have a license as a DMT in MS. However, it has very good NEDA data and I suspect it would as efficacious, if not more efficacious, than fingolimod. This makes my recent post on the off-label use of cladribine in resource poor countries very pertinent to this post. I really wish we could resuscitate cladribine and get it a licensed as an alternative option for the treatment of RRMS. Oral cladribine has so many positive attributes; it is orally administered as short courses, it is an induction therapy, it ideal treatment for woman wanting to start, or extend their families, side effects are low, it is well tolerated, adherence is really not an issue and there is no secondary autoimmunity. Even the short-term malignancy scare appears to have disappeared although it is likely that long-term risks will remain an issue. The big issues are infection risks and persistent lymphopaenia; these are really problems across many DMTs and we know how to handle them. I hope Merck-Serono or a White Knight is reading this post."

“When reading and assimilating information from this post, please note my conflicts of
interest below. I may be biased, but the data is what it is.”

INTRODUCTION: No head-to-head trials have compared the efficacy of the oral therapies, fingolimod, dimethyl fumarate and teriflunomide, in multiple sclerosis. Statistical modeling approaches, which control for differences in patient characteristics, can improve indirect comparisons of the efficacy of these therapies.

METHODS: No evidence of disease activity (NEDA) was evaluated as the proportion of MSers free from relapses and 3-month confirmed disability progression (clinical composite), free from gadolinium-enhancing T1 lesions and new or newly enlarged T2 lesions (magnetic resonance imaging composite), or free from all disease measures (overall composite). For each measure, the efficacy of fingolimod was estimated by analyzing individual patient data from fingolimod phase 3 trials using methodologies from studies of other oral therapies. These data were then used to build binomial regression models, which adjusted for differences in baseline characteristics between the studies. Models predicted the indirect relative risk of achieving NEDA status for fingolimod versus dimethyl fumarate or teriflunomide in an average patient from their respective phase 3 trials.

Monday, 24 November 2014

I was giving a talk about animal models and their role in developing drugs to MS and I was asked by someone from Finland to post on this subject.

As you may know only two drugs (out of about two thousand tried) have their routes in animal MS models and these are glaterimer acetate and Tysabri, where their action was first found in MS models.

However in recent time I would bet that in most cases, MS drugs have been tried in MS models as part of the development pathway. Furthermore, we have to be aware that the development pathway for a drug is along time and many of those drugs active in animals may be things for the future.

But how do we get drugs to people with MS?

We can invent a drug and take it through the full development process (See Drug the Board Game). This takes about 10-15 years with pharma driving this. For my symptom control drug without sedative side-effects (work not yet published).....it has been 12 years so far (first experiment done 25:11:2002 and we had to invent and make the compound first) and we still have phase II/III and licensing to go.

The quick way to develop drugs is to repurpose a drug. Here the idea is to take a drug that has been through the full development process for another disease so it is known to be safe in humans and then use the drug in MS to show it works and is safe and Bobs your uncle you have an MS drug...so that's the theory.

The Wellcome Trust and the Department of Health in the UK and the National Institute of Health have been putting millions into this process. However, I wonder if any of them have really thought the process through. Can we really repurpose drugs for MS?

There are two ways of repurposing the academic way and the pharma way.

THE ACADEMIC WAY

The academic way..is to take a cheap drug and then do a trial as academics are good at doing trials...but then what?

For a rapidly life threatening condition it is easier to push things forward...take the new anti-ebola virus drugs. For Chronic diseases the hurdles are higher.

Academics sit on committees like the FDA and have said to industry we don't believe your trial so go away and do another one and then hold a licence and have a safety monitoring structure and this all adds to the cost and the time taken to develop drugs.

Industry are going to say to academic neuros..... fine do a trial, but it should be a level playing field and so academics need to do the process properly just as pharma are made do it.

Could an academic get funded to do the same trial twice? I doubt any grant agency would support this. Some academics think that you do a trial and ever one will believe their data and prescribe the drug.

Is this Hope or False Hope or Bob Hope?

More likely it will show pharma what drugs could work in MS and they will then go into their drug libraries and come up with a new patented drugs or will repurpose the pharma way.

However, what have academic Neuros delivered.....lots of trials...but so far no drugs in recent history, unless pharma are involved!

So here is the challenge for all academic Neuros doing clinical trials...how do you get your repurposed drug to people with MS?

If it can't be realistically done, is it ethical to start?If it can't be done, what needs to put in place to make this happen?This may need changes in Government policy

If Governments would protect industry such that they can recoup their trial costs etc with a generic drug there will be an incentive to really repurpose drugs.

However, MS pharma have been repurposing drugs for years and this is the MS way.

THE PHARMA WAYThe pharma way to repurposing is to find a drug that is safe in humans and then get a patent on it.

This may mean taking a drug that works in another disease and re-engineer them to make them work in MS.

This repurposing approach is so successful that MS pharma is repurposing its own drugs. Such that we have pegylated interferon to replace interferon and Copaxone three times a week (tiw) to replace Copaxone once a day (qd).

Funny that these drugs arrive as the patent for the founder drugs expire....Will we get a new tysabri once every 6 months in the future or the anti-CD49d pill?

However, the pharma way to repurposing can be more simple, take a drug and make it hang round in the system for longer e.g. Fampryidine from 4-amino pyridine.

They may spend millions taking a generic drug then re-engineering it to make a patented drug. For example making a pro-drug which converts into the active metabolite or just developing the active metabolite like, Aubagio.

What does this say...well the generic parent drug will be active also eg. Leflunoamide

Should academics show this, to deliver cheap MS drugs to the world? They could do the reverse development (reverse purposing) and take an active pharma drug and show that the generic drug works.

However, if they use the academic way ...what will this deliver based on past record? As many of the readers of the Blog are Neuros...This is your challenge that needs change.

There was a comment last week chartising Pharma Neuros, but as they point out at least they can say that they are helping delivering treatments to people. Can academic neuros get this reward for their labours?

How do you change the academic way so that it actually delivers useful treatments for people with MS?

This is important as we are in a process of hunting for neuroprotectant and repair agents using repurposing

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Holistic Management of MS ver. 7.0

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